I discovered this article today from the American Academy of Neurology - as news from their annual meeting.

This is a fairly well know genetic mutation (GBA) that causes Gaucher Disease. Two studies haved linked this mutation to being a significant risk factor in developing PD or any Lewy Body Disorder: "carriers of the mutation were signifcantly more likely than non-carriers to have a clinical diagnosis of PD or Lewy Body dementia".

One promotional message:
Obviously brain donation made this research possible.

Other comments:
One goal with research into gene mutations is to find biomarkers that can be used to identify who is at high risk of acquiring LBD (or PD or any disorder) later in life. One of the researchers quoted in the article said the following: "In the future, it may be possible to identify a much purer diagnosis of Lewy Body disorders if the patient has a GBA mutation," Dr. Marder said. "But we're still far from saying people should get genetic testing for this."

The article refers to the pathological diagnosis of "incidental Lewy bodies." I believe this is the pathological diagnosis given to someone who has the clinical diagnosis of PD.

A body of work has emerged over the past decade demonstrating a relationship between mutations in glucocerebrosidase gene (GBA), the gene implicated in Gaucher disease (GD), and the development of parkinsonism. Several different lines of research support this relationship. First, patients with GD who are homozygous for mutations in GBA have a higher than expected propensity to develop Parkinson's disease (PD). Furthermore, carriers of GBA mutations, particularly family members of patients with GD, have displayed an increased rate of parkinsonism. Subsequently, investigators from centers around the world screened cohorts of patients with parkinsonism for GBA mutations and found that overall, subjects with PD, as well as other Lewy body disorders, have at least a fivefold increase in the number of carriers of GBA mutations as compared to age-matched controls. In addition, neuropathologic studies of subjects with parkinsonism carrying GBA mutations demonstrate Lewy bodies, depletion of neurons of the substantia nigra, and involvement of hippocampal layers CA2-4. Although the basis for this association has yet to be elucidated, evidence continues to support the role of GBA as a PD risk factor across different centers, synucleinopathies, and ethnicities. Further studies of the association between GD and parkinsonism will stimulate new insights into the pathophysiology of the two disorders and will prove crucial for both genetic counseling of patients and family members and the design of relevant therapeutic strategies for specific patients with parkinsonism.

PubMed ID: 19425057 (see pubmed.gov for abstract only; you can link to the publisher's website to purchase the full article for perhaps $30)

Several in the local support group emailed me about this news today. Some sent the HealthDay article, and one sent the NIH press release. The article reports on a worldwide study clinching "the case that the gene behind Gaucher disease, a rare neurological disorder, is also involved in Parkinson's disease." Key excerpts:

* Gaucher disease develops in people who have two defective copies of a gene designated GBA. It codes for production of an enzyme that breaks down glucocerebrosidase, a fatty substance normally found in the body. The faulty gene allows accumulation of the substance, which can harm the spleen, liver, lungs, bone marrow and even the brain.

* "This gene plays a more common role in Parkinson's than other genes, but it is not necessarily predictive of Parkinson's disease. It is a risk factor rather than a gene that predicts the disease," [one of the researchers said.]

* Several smaller studies have suggested the genetic link between the two conditions, "but there have always been questions based on their size and controls," Sidransky said. "Once and for all, we have put together a large enough number so that no one will question the results."

The HealthDay article follows along with the abstract of the NEJM-published study and the NIH press release.

Gene Behind Gaucher Disease a Player in Parkinson's
Finding from worldwide study could one day lead to new treatments

By Ed Edelson, HealthDay Reporter

WEDNESDAY, Oct. 21 (HealthDay News) -- An unprecedented worldwide study has clinched the case that the gene behind Gaucher disease, a rare neurological disorder, is also involved in Parkinson's disease.

"For those of us who work with rare disorders, it is heartwarming to come up with insights that are applicable to more common disorders," said Dr. Ellen Sidransky, a senior investigator in the U.S. National Human Genome Research Institute, and leader of a study reported in the Oct. 22 issue of the New England Journal of Medicine.

Gaucher disease affects no more than one in 100,000 people in most populations, with an estimated 5,400 cases in the United States. As many as 3 million to 4 million Americans are estimated to have Parkinson's disease.

Gaucher disease develops in people who have two defective copies of a gene designated GBA. It codes for production of an enzyme that breaks down glucocerebrosidase, a fatty substance normally found in the body. The faulty gene allows accumulation of the substance, which can harm the spleen, liver, lungs, bone marrow and even the brain.

Discovery that the two conditions have a common genetic element cannot be applied immediately to relieve the stiffness, trembling and other symptoms of Parkinson's disease, Sidransky said.

"We have to be cautious about jumping into clinical applications," she said. "This gene plays a more common role in Parkinson's than other genes, but it is not necessarily predictive of Parkinson's disease. It is a risk factor rather than a gene that predicts the disease."

"The work will teach us about the mechanisms of Parkinson's disease, and once we understand the mechanisms we can come up with therapies that can help patients with Parkinson's disease. And it could ultimately lead to better therapies that could help patients with Gaucher disease," Sidransky said.

Several smaller studies have suggested the genetic link between the two conditions, "but there have always been questions based on their size and controls," Sidransky said. "Once and for all, we have put together a large enough number so that no one will question the results."

The study she led involved 16 institutions around the world. A listing of the institutions and researchers filled a complete page on the journal in fine print.

Those researchers examined the frequency of GBA variants in 5,691 people with Parkinson's disease, including 780 Ashkenazi Jews, an ethnic group in which Gaucher disease is more common. Their data was matched with genetic information from 4,898 disease-free individuals, including 387 Ashkenazi Jews.

At least one of two common GBA variants was found in 3.2 percent of the people with Parkinson's disease, but only 0.6 percent of the disease-free individuals. Among the Ashkenazi participants, 15.3 percent of those with Parkinson's disease carried a GBA variant, compared to 3.4 percent of disease-free Ashkenazi individuals.

In addition to increasing the risk of Parkinson's disease, presence of a GBA variant was associated with early onset of the condition, four to five years sooner than ordinarily seen, the study found.

"Its importance is that it may indicate a new pathway to explore for the etiology [cause] of Parkinson's disease, and ultimately a target for drug discovery," said Dr. Karen Marder, a professor of neurology at Columbia University Medical Center, and one of the researchers in the trial.

The discovery raises some possible issues about genetic counseling, Marder said, but more work must be done before that can influence medical practice.

"This is among the most important susceptibility factors for Parkinson's that has ever been discovered, but it is premature to talk about using it in clinical practice," she said.

More information

Symptoms and treatment of Parkinson's disease are described by the U.S. National Institute of Neurological Disorders and Stroke.

NIH News
The National Human Genome Research Institute (NHGRI)
Wednesday, October 21, 2009

Study Conclusively Ties Rare Disease Gene to Parkinson's
Risk of Parkinson's Disease Is Five Times Greater for Gaucher Disease Carriers

An international team led by a National Institutes of Health researcher has found that carriers of a rare, genetic condition called Gaucher disease face a risk of developing Parkinsonâs disease more than five times greater than the general public. The findings were published today in the New England Journal of Medicine.

In previous studies, several genes have been linked to Parkinson's disease. However, researchers say their work conclusively shows that mutations in the gene responsible for Gaucher disease are among the most significant risk factors found to date for Parkinson's disease. The discovery was made by investigators from the National Human Genome Research Institute (NHGRI) and the National Institute on Aging (NIA), both parts of the National Institutes of Health, in collaboration with scientists from 16 research centers across four continents.

"This analysis illustrates how studying a rare but important disorder, like Gaucher disease, can provide powerful clues about more common disorders, such as Parkinson's disease," said NHGRI Scientific Director Eric Green, M.D., Ph.D. "Understanding the genetic basis of rare conditions can thus provide insights into normal cellular and biological processes, which in turn may lead to improved diagnostic and therapeutic strategies."

Parkinson's disease, a neurological condition that typically causes tremors and stiffness in movement, affects about 1 to 2 percent of people over the age of 60. The chance of developing Parkinson's disease increases with age and involves a combination of environmental risk factors and genetic susceptibility.

Gaucher disease occurs when an individual inherits two defective copies of the GBA gene, which codes for an enzyme called glucocerebrosidase. This enzyme breaks down a fatty substance called glucocerebroside, which, when not properly disposed of, can harm the spleen, liver, lungs, bone marrow and, in some cases, the brain. The enzyme functions in a part of the cell called the lysosome, where cellular components are broken down, or metabolized, for recycling.

In the past, it was thought that people who carry just one altered GBA gene were unaffected. However, in recent years, research groups at NHGRI and elsewhere have completed small studies suggesting that carriers of GBA alterations may have an increased risk of developing Parkinson's disease.

"The opportunity was right to amass the data into one powerful study," said Ellen Sidransky, M.D., senior investigator in NHGRI's Medical Genetics Branch, who is the lead author of the study and coordinated the effort. "Our analyses of the accumulated data provide a convincing association between GBA alterations and Parkinson's disease."

The research team examined the frequency of GBA alterations in 5,691 patients with Parkinson's disease, including 780 Ashkenazi Jews, a population in which a particular type of Gaucher disease is more prevalent. Those data were matched against 4,898 unaffected volunteers, called controls, which included 387 Ashkenazi Jews.

At least one of the two common GBA alterations was found in 3.2 percent of Parkinson's patients and 0.6 percent of controls. Among the Ashkenazi subjects, 15.3 percent of those with Parkinson's disease carried a GBA alteration compared to 3.4 percent of Ashkenazi controls.

In addition to screening for the two common alterations, five of the research centers sequenced the entire GBA gene in 1,642 non-Ashkenazi patients with Parkinson's disease and 609 non-Ashkenazi controls. Using this more thorough method, they found many additional alterations associated with Parkinsonâs disease, and showed that 7 percent of patients carried an alteration, indicating that it is important to look beyond the two common alterations to gain a true picture of risk in the general population.

Besides significantly increasing the risk of Parkinson's disease, GBA alterations also appear to increase the likelihood of early disease onset. According to the new study, Parkinson's patients with GBA alterations developed symptoms an average of four years earlier than other Parkinson's patients.

Overall, the researchers found that the association between GBA and Parkinsonâs disease is not confined to any single ethnicity or to specific GBA mutations, though they did find that some gene alterations are seen more frequently in certain populations. Compared with the general population, in which GBA alterations occur in fewer than one out of 100 people, GBA alterations occur in at least one out of 16 people of Ashkenazi descent. However, many GBA mutation carriers as well as patients with Gaucher disease never develop Parkinson's disease, so this appears to be only one of several risk factors involved.

Further research is in progress to understand the full spectrum GBA alterations, their biological significance and their association with both Parkinson's and Gaucher disease. The researchers are also pursuing ways to provide more accurate guidance based on the findings for genetic counseling and for the development of new therapeutic strategies for these disorders.

Along with NIH, the study included research centers in New York City, Jacksonville, Fla. and Seattle, as well as in Brazil, Canada, France, Germany, Israel, Italy, Japan, Norway, Portugal Singapore and Taiwan. The data were collected and analyzed at NHGRI.

The NIA leads the federal effort supporting and conducting research on aging and the medical, social and behavioral issues of older people. For more information on research and aging, go to www.nia.nih.gov.

NHGRI is one of the 27 institutes and centers at the NIH, an agency of the Department of Health and Human Services. The NHGRI Division of Intramural Research develops and implements technology to understand, diagnose and treat genomic and genetic diseases. Additional information about NHGRI can be found at its Web site, www.genome.gov.

The National Institutes of Health (NIH) â The Nation's Medical Research Agency â includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. It is the primary federal agency for conducting and supporting basic, clinical and translational medical research, and it investigates the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit www.nih.gov.

Background
Recent studies indicate an increased frequency of mutations in the gene encoding glucocerebrosidase (GBA), a deficiency of which causes Gaucher's disease, among patients with Parkinson's disease. We aimed to ascertain the frequency of GBA mutations in an ethnically diverse group of patients with Parkinson's disease.

Methods
Sixteen centers participated in our international, collaborative study: five from the Americas, six from Europe, two from Israel, and three from Asia. Each center genotyped a standard DNA panel to permit comparison of the genotyping results across centers. Genotypes and phenotypic data from a total of 5691 patients with Parkinson's disease (780 Ashkenazi Jews) and 4898 controls (387 Ashkenazi Jews) were analyzed, with multivariate logistic-regression models and the MantelÂ­Haenszel procedure used to estimate odds ratios across centers.

Results
All 16 centers could detect two GBA mutations, L444P and N370S. Among Ashkenazi Jewish subjects, either mutation was found in 15% of patients and 3% of controls, and among nonÂ­Ashkenazi Jewish subjects, either mutation was found in 3% of patients and less than 1% of controls. GBA was fully sequenced for 1883 nonÂ­Ashkenazi Jewish patients, and mutations were identified in 7%, showing that limited mutation screening can miss half the mutant alleles. The odds ratio for any GBA mutation in patients versus controls was 5.43 across centers. As compared with patients who did not carry a GBA mutation, those with a GBA mutation presented earlier with the disease, were more likely to have affected relatives, and were more likely to have atypical clinical manifestations.

Conclusions
Data collected from 16 centers demonstrate that there is a strong association between GBA mutations and Parkinson's disease.

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